Aging is the most important risk factor for major chronic diseases and disability. In prior work, we found that variation in the FOXO3 gene (the human homolog of the C. elegans daf-16 gene) was strongly associated with healthy aging and longevity in the Kuakini Honolulu Heart Program (Kuakini HHP) cohort. The protective effect on longevity has since been replicated in numerous populations and FOXO3 is now one of only two genes that have consistent replications across populations for human longevity. Yet, the mechanism is not known on a disease-specific basis or a molecular basis. In preliminary work, we found that FOXO3 strongly protects against Cardiovascular Disease (CVD), Vascular Cognitive Impairment and Dementia (VCID) - important causes of death and disability at older ages. Our data also suggest that a FOXO3-driven anti-inflammatory pathway may be an important cell and molecular mechanism for protection against age-related diseases and disability ? particularly vascular-related diseases. This renewal proposal assesses whether InflammAging (aging-related inflammation) is modulated by FOXO3 genotype and whether this impacts risk for CVD, Alzheimer?s disease (AD), and VCID. To test this hypothesis, we propose the following Specific Aims: AIM 1. CONDUCT a prospective study of FOXO3 genotype on incident disease and mortality across most of the adult lifespan. Hypothesis: FOXO3 enhances longevity over the adult lifespan principally through protection against vascular disease. AIM 2. TEST whether carriers of the longevity-associated FOXO3 allele have a protective anti- inflammatory serum profile. Hypothesis: FOXO3 reduces mortality through a cytokine-mediated anti-inflammatory pathway. AIM 3. TEST whether FOXO3 genotype influences cognitive aging, AD and VCID. Hypothesis: Gene variants that promote longevity may also promote healthy brain aging, including better cognitive function, less brain pathology on autopsy and lower rates of incident AD and VCID. Inflammation may be a mediating factor.